The main focus of this grant is to examine the role of transient receptor potential-vanilloid (TRPV) channels and endocannabinoid transmitters on modulating nociceptive signaling in invertebrates. Recent studies have shown that TRPV receptors modulate endocannabinoid-dependent processes, including nociceptive signaling (1,14). It is possible that TRPV receptors mediate ecLTD in nociceptive neurons through low-frequency stimulation (LFS) of a non-nociceptive pathway. This mechanism parallels the gating control theory of pain, where stimulation of a non-nociceptive pathway attenuates the nociceptive pathway (37). In leech central synapses, both nociceptive sensory neurons (N-cells) and non-nociceptive touch neurons (T-cells) have synaptic input onto the same postsynaptic longitudinal motor neuron (L-cells). This grant proposal will examine whether attenuation of the nociceptive N-to-L pathway can be induced through a LFS of the non-nociceptive T-to-L pathway and whether this ecLTD is mediated by TRPV-like receptors. Endocannabinoids are traditionally synthesized in the postsynaptic cell and travel in a retrograde fashion, binding to their receptors on the presynaptic side (1). Evidence suggests TRPV receptors mediate signaling on the presynaptic locus (2); therefore, it is possible that endocannabinoids bind to TRPV receptors on the presynaptic neuron, facilitating ecLTD. This grant proposal will also examine the functional role of TRPV receptors on nociceptive signaling through a behavioral viewpoint. In the leech, the whole body shortening reflex will be utilized to examine through intracellular N-cell stimulation whether this response can be attenuated through activation of endocannabinoids and LFS. Through pharmacological, physiological, and behavioral methods, this proposal can provide a better understanding on the role of TRPV receptors in mediating ecLTD at nociceptive pathways, leading to therapeutic implications at the clinical level. The level of training will be for a pre-doctoral student with the duration of two to three years of training. The projected number of trainees only includes the fellowship applicant with the sponsor providing the necessary training based on his years of experience. The fellowship applicant has already had three years of experience in electrophysiology techniques, but behavioral and iontophoresis techniques will bring new challenges to this applicant, creating an opportunity to bring new directions and perspectives into this research proposal. In a global context, this training plan will address fundamental issues regarding nociception and its mechanisms. With pain disorders affecting millions of Americans, understanding the underlying basis of nociceptive signaling is an essential aspect of both mental and physical health. Treatment and management are enormously important for individuals suffering from pain disorders and gaining further knowledge on pain signaling mechanisms through bench research could lead to further treatment therapies at the bedside.